Preventing Hypertension and Sympathetic Overactivation by Targeting Phosphate

Sponsor

University of Texas Southwestern Medical Center (Other)

Overall Status

Recruiting

CT.gov ID

NCT03234361

Collaborator

(none)

114

Enrollment

Locations

Arms

59.5

Anticipated Duration (Months)

Patients Per Site

0.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

An increasing number of studies have indicated that most fast food and common grocery items, contain large amount of inorganic phosphate-based food additives , which are highly absorbable. The long-term cardiovascular consequences of a high phosphate diet are unknown but the existing database implicates phosphate excess as an independent risk factor for cardiovascular events in individuals with and without chronic kidney diseases (CKD). High phosphate consumption clearly induces BP elevation in rats with normal kidneys. However, the mechanisms underlying phosphate-induced hypertension and the relevance of these rodent studies to human hypertension have not been determined. We seek to investigate the role of high phosphate diet in human hypertension and assess the effect of high phosphate diet on muscle sympathetic nerve activity and the exercise pressor reflex.

Condition or Disease	Intervention/Treatment	Phase
Hypertension	Dietary Supplement: High Phosphate Phase Dietary Supplement: Low Phosphate Phase	Phase 2

Detailed Description

Animal studies suggest that high phosphate diet raises blood pressure but the mechanism underlying this phenomenon is not known. To study the effect of high phosphorus diet on blood pressure in humans, we will perform randomized crossover studies in stage 1 prehypertensive subjects. To ensure stable Pi intake prior to randomization, Pi consumption will be estimated by food recall during a run-in and washout phase for 2 consecutive days, using the Automated Self-Administered 24-Hour (ASA24®) Dietary Assessment Tool (https://epi.grants.cancer.gov/asa24/). After the run-in period, all subjects will be maintained on a low Pi diet (700 mg/d) and a low Na diet of approximately 1,930 mg/d throughout the study for 8 weeks. Subjects will also be randomized to receive Sodium Phosphate 2 capsules daily (containing a total of 500 mg of Pi, 372mg of sodium) for 4 weeks during the high Pi phase (total Pi intake 1,200 mg/d) vs 2 capsules of Sodium Chloride (NaCl, containing a total of 372mg of sodium) to match Na content to Sodium Phosphate without extra Pi daily for 4 weeks during the low Pi phase (total Pi intake = 700 mg/d).

The total Na intake during the entire study will be at recommended level of 2,300 mg/d. Investigational drug service at UT Southwestern will dispense Sodium Phosphate vs. NaCl tablets tablets and the study subjects will be blinded to the type of supplement they receive.

During the periods of high and low Pi phases, we will monitor 24-hr UPiV to ensure adherence. Since approximately 70% of ingested Pi is absorbed and excreted in the urine, we expect 24-hr UPiV excretion to be approximately 840 mg during the high Pi phase and 490 mg during the low Pi phase. If 24-hr UPiV is < 800 mg during the high Pi diet or > 500 mg during the low Pi diet, the research dietitian will provide additional counseling to improve adherence to the menu plan. If needed, the research diet will be altered to be more compatible with subject preference. 24-hr UPiV will be reassessed within 1 week in these individuals. If the levels remain below goal, subjects will be excluded from the study.

24-hr urinary Pi, Na, K, Cr, and Ca excretion will be assessed after weeks 2 and 4 of the low and high Pi phases. Serum electrolytes and Pi will be monitored every 2 weeks. Serum FGF23, PTH, and soluble Klotho levels and 24-h ambulatory BP will be obtained after 4 weeks on the study diet. Then, on a separate day, we will assess muscle SNA and BP at rest and during rhythmic handgrip of 30% and 45% each for 3 minutes. Additionally, we will test the role of dietary Pi on the response to isometric exercise by assessing SNA and BP during static handgrip at 30% MVC for 2 minutes followed by post exercise circulatory arrest (PECA). The latter maneuver will maximally activate the metaboreflex. Each exercise intervention will be separated by at least 30 minutes. The order of exercise intervention will be randomized. Subsequently, subjects will stop the first study supplement and undergo washout for 2 weeks. After 2 weeks of washout, they will receive the 2nd study supplement. Measurement of 24-h ambulatory BP, SNA at rest and during handgrip exercise will be repeated in the same fashion.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

114 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

Preventing Hypertension and Sympathetic Overactivation by Targeting Phosphate

Actual Study Start Date :

Oct 16, 2017

Anticipated Primary Completion Date :

Sep 30, 2022

Anticipated Study Completion Date :

Sep 30, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: High Phosphate Phase All subjects will be on a low Pi diet containing 700mg/day of phosphate and 2 capsules of sodium phosphate with 500mg/day of phosphate for 4 weeks.	Dietary Supplement: High Phosphate Phase 2 capsules of sodium phosphate with 500mg/day of phosphate.
Placebo Comparator: Low Phosphate Phase All subjects will be on a low Pi diet containing 700mg/day of phosphate and 2 capsules of sodium chloride for 4 weeks.	Dietary Supplement: Low Phosphate Phase 2 capsules of sodium chloride.

Arm

Intervention/Treatment

Experimental: High Phosphate Phase

All subjects will be on a low Pi diet containing 700mg/day of phosphate and 2 capsules of sodium phosphate with 500mg/day of phosphate for 4 weeks.

Dietary Supplement: High Phosphate Phase

2 capsules of sodium phosphate with 500mg/day of phosphate.

Placebo Comparator: Low Phosphate Phase

All subjects will be on a low Pi diet containing 700mg/day of phosphate and 2 capsules of sodium chloride for 4 weeks.

Dietary Supplement: Low Phosphate Phase

2 capsules of sodium chloride.

Outcome Measures

Primary Outcome Measures

24-hour Blood Pressure measured by Ambulatory Blood Pressure Monitor. [4 weeks]
Blood pressure will be measured through an ambulatory blood pressure monitoring device by Space Labs # 90217, worn by each participant after completing each phase, This will suggest if participant's blood pressure increased during high phosphorus phase as compared to low phosphorus phase.

Secondary Outcome Measures

Muscle Sympathetic Nerve Activity (MSNA) [4 weeks after high phosphorus and 4 weeks after low phosphorus diet]
MSNA will be measured during both diet phases using microelectrodes inserted in the peroneal nerve. This will assess the impact of phosphate intake on MSNA.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria: (answer must be yes to all to enter trial; check yes or no)

º ≥ 18 years of age

º Stage 1 Prehypertension (office BP 120-129/80-84 mmHg and normal ABPM <130/80)

Exclusion Criteria: (answer must be no to all to enter trial)

º Diabetes mellitus or other systemic disease

º Cardiopulmonary disease

º Treatment with antihypertensive medications

º eGFR< 60 ml/min/1.73m2

º Pregnancy

º Hypersensitivity to nitroprusside or phenylephrine

º Psychiatric illness

º H/o substance abuse or current smoker

º H/o malignancy

º Serum Phos <2.4 mg/dL or >4.5 mg/dL

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Texas Southwestern Medical Center at Dallas	Dallas	Texas	United States	75390
2	University of Texas Southwestern Medical Center at Dallas	Dallas	Texas	United States	75390
3	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390